Article pubs.acs.org/joc
Regioselective Ortho Olefination of Aryl Sulfonamide via RhodiumCatalyzed Direct C−H Bond Activation Weijia Xie,† Jie Yang,† Baiquan Wang,*,†,‡ and Bin Li*,† †
State Key Laboratory of Element-Organic Chemistry, Synergetic Innovation Center of Chemical Science and Engineering, College of Chemistry, Nankai University, Tianjin 300071, People’s Republic of China ‡ State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People’s Republic of China S Supporting Information *
ABSTRACT: Rh(III)-catalyzed ortho C−H olefination of aryl sulfonamide directed by the SO2NHAc group is reported. This oxidative coupling process is achieved highly efficiently and selectively with a broad substrate scope. The reactions of Ntosylacetamide with acrylate esters afford ortho-alkenylated benzofused five-membered cyclic sulfonamides, whereas styrenes provide the direct diolefination products.
■
INTRODUCTION Transition-metal-catalyzed C−H functionalization of arenes represents a step-economical and waste-reducing process, because no prior functionalization of the substrate is necessary.1 Its synthetic applications have been well identified in the fields of organic synthesis, medicinal chemistry, and materials science.2 In this regard, the Fujiwara−Moritani reaction3 oxidative olefination of normally inert aryl C−H bondsis an attractive alternative to the traditional Mizoroki−Heck reaction.4 Among such transformations, palladium(II) complexes have been extensively explored and widely used due to their remarkable activities.5 Later, after the pioneering work of Satoh and Miura, rhodium(III)6 and ruthenium(II)7,8 species were also found to exhibit high catalytic activity in the oxidative alkenylation reactions. In these reactions, the utility of a neighboring directing group has proven to be one of the most promising strategies for ensuring regioselective C−H activation.9 Sulfonamide functional groups have long been acclaimed as essential structural motifs presented in drugs such as darunavir, celecoxib, and gliclazide.10 Meanwhile, sultams (cyclic sulfonamides) have emerged as privileged structures in drug discovery due to their diverse biological properties.11 In particular, a number of benzofused sultams have shown promising bioactivity for treating disorders of the brain12 and exhibit broad inhibitory properties against a variety of enzymes (Figure 1).13 Recent studies reveal that the sulfonamide group can act as a directing group in promoting C−H activation; however, only very limited examples have been documented.14,15 In 1998, Miura demonstrated the olefination reaction of N-(2′-phenylphenyl)benzenesulfonamides with acrylate esters via cleavage of the C−H bond at the 2′position.15a In 2011, Li reported a rhodium(III)-catalyzed C−H © XXXX American Chemical Society
Figure 1. Biologically active molecules containing the sulfonamide or sultam substructure motif.
olefination of N-(1-naphthyl)sulfonamides at the peri position.15b Later, this group described a Rh(III)-catalyzed oxidative coupling between N-allyl sulfonamides with activated olefins.15c For these substrates, the C−H bonds of arenes connected to sulfonamide sulfur atoms are totally inert under the reaction conditions (Scheme 1). With the assistance of SO2NHC6F5 as a directing group, Yu reported Pd-catalyzed sulfonamide C−H olefination. The reactions only produce direct alkenylation products, irrespective of the alkenes employed (Scheme 1a).15d As a continuation of our interest in Ru- and Rh-catalyzed C−H functionalization,16 we herein disclose our recent development of Rh-catalyzed regioselective oxidative C−H olefination using SO2NHAc as a directing Received: July 9, 2014
A
dx.doi.org/10.1021/jo5015239 | J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry
Article
Scheme 1. Sulfonamide Group Directed Oxidative Olefination
Table 1. Optimization of Oxidative Coupling between 1a and 2aa
catalyst
oxidant (amt (equiv))
solvent
yield (%)b
1 2 3 4 5 6
[Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2
toluene DME CH3CN toluene toluene toluene
99 (93)c 10 NR trace 48 trace
7 8 9 10 11 12
[Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*Rh(OAc)2] [Cp*RhCl2]2/ AgSbF6 none [Ru(p-cymene) Cl2]2
Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O Ag2CO3 AgOAc Cu(OAc)2·H2O (0.5) + O2 Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O
toluene toluene toluene toluene toluene toluene
82d 54e 40f NRg 65h NRi
Cu(OAc)2·H2O Cu(OAc)2·H2O
toluene toluene
NR NR
entry
group. The reactions afford ortho-alkenylated benzofused sultam analogues and diolefinated aryl sulfonamides with good yields and a broad reaction scope (Scheme 1b).
13 14
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a Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol). bYield determined by 1H NMR (internal standard: 1,1,2,2-tetrachloroethane). NR = no reaction. cValue in parentheses indicates yield after purification. d2.0 mol % of [Cp*RhCl2]2 was used. e1a:2a (1:1); the monoalkenylated cycloadduct was also formed in 16% yield. f1a:2a (2:1), 2a (0.3 mmol); the monoalkenylated cycloadduct was also formed in 25% yield. g80 °C. h4.0 mol % of [Cp*Rh(OAc)2] was used. i 12.0 mol % of AgSbF6 was used.
RESULTS AND DISCUSSION We initiated our study with the oxidative olefination of readily available N-tosylacetamide (1a) and ethyl acrylate (2a). After a considerable number of experiments (Table 1),17 we found that product 3a, which was formed by dialkenylation at both ortho positions followed by intramolecular hydroamination, was obtained in 93% yield in the presence of [Cp*RhCl2]2 (3.0 mol %) and Cu(OAc)2·H2O (2.0 equiv) in toluene at 100 °C under an Ar atmosphere for 24 h (entry 1, Table 1). No monoalkenylated cycloadduct was observed. The structure of 3a was confirmed by 1H and 13C NMR analysis and mass spectrometry. The solvents DME and CH3CN exhibited negative results (entries 2 and 3). A change of oxidant to AgOAc, Ag2CO3, or O2 led to a low yield or a trace amount of the desired product (entries 4−6). Reducing the amount of [Cp*RhCl2]2 from 3.0 to 2.0 mol % provided 3a in 82% yield (entry 7). It is interesting to find that when switching the ratio of 1a and 2a to 1:1 and 2:1, the reactions still gave dominantly the dialkenylation product 3a and the monoalkenylated cycloadduct was detected in 16% and 25% yields by 1H NMR, respectively (entries 8 and 9). The reaction efficiency was also sensitive to the reaction temperatures (entry 10). Some other rhodium complexes were also screened. For example, when [Cp*Rh(OAc)2] was applied as a catalyst, the reaction still afforded dialkenylation product 3a, albeit in relatively lower yield (entry 11). However, the cationic rhodium species [Cp*Rh(MeCN)3][SbF6]2, generated in situ by the addition of AgSbF6, totally inhibited the reaction (entry 12). A control experiment confirmed that the transformation did not proceed in the absence of the rhodium catalyst (entry 13). Finally, [Ru(p-cymene)Cl2]2 displayed no catalytic activity under the present reaction conditions (entry 14). With the promising optimal conditions, we first investigated the influence of different substituents on the sulfonamide nitrogen atom (Scheme 2). In addition to the acetyl group, the butyryl group was also well suited and gave the product 3b
under the optimized reaction conditions in 97% yield. However, the pivaloyl, N-methoxy, and N-acrylyl derivatives were completely unreactive. We next examined the scope of aryl sulfonamides with diverse arene substituents (Scheme 2). Gratifyingly, the reaction proceeded smoothly irrespective of the electronic nature of the substituents to afford the desired products in good to excellent yields. Many important functional groups, such as fluoro, chloro, bromo, methoxy, trifluoromethoxy, and ester substituents, were compatible in the present catalytic reaction (3d−i). Surprisingly, in addition to the desired product 3j, a substrate with a nitro substituent also afforded the nitro group reduced byproduct 3k in 16% yield. This result suggested that the nitro group might partially act as an oxidant in this reaction. The meta-substituted substrates were then studied. Both naphthalen-2-yl and 3-bromophenyl sulfonyl acetamide reacted with acrylates to form 3l−n as the sole products. Interestingly, the cyclizations occurred at the sterically more hindered position in compounds 3l−n, which were confirmed by NOESY spectroscopy of 3l,m.17 The exact reason for the selective ring formation is not clear yet, although it seems that the adjacent steric hindrance of meta-substituted group to the alkene could be partially involved. Notably, a substrate bearing a 3-CF3 moiety underwent the olefination to provide monoolefinic products 4a,b in moderate yield. The monofunctionalization in 4a,b might result from the combined electronic and steric effects of the meta-substituted CF3 group. Ortho-substituted aryl sulfonamides coupled with ethyl acrylate B
dx.doi.org/10.1021/jo5015239 | J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry
Article
Scheme 2. Rhodium-Catalyzed Oxidative C−H Olefination with Acrylic Acid Estersa
a Reaction on a 0.3 mmol scale. Yields of isolated products are given. NR = no reaction. bThe value in parentheses indicates the yield of the reaction on a 3.0 mmol scale. c5.0 mol % of [Cp*RhCI2]2 was used. d2.0 equiv of 2 was used. eAt 120 °C.
the dialkenylated derivative 6a in 81% yield (entry 1, Table 2). In this reaction, no cyclization process occurred. Under the reaction conditions, various substituted styrenes with either electron-donating or -withdrawing groups were good candidates and produced the corresponding products 6b−h in moderate to high yield (entries 2−8). The reaction is also tolerant of different substitutions on the aromatic sulfonamides. For example, 4-chloro- and 4-methoxy-substituted aryl sulfonamides also reacted well with 5a (entries 9 and 10). Examination of the meta-substituted substrate scope revealed that 3-bromophenyl sulfonyl acetamide only produced dialkenylated derivative 6k, albeit in low yield (entry 11). However, the reaction of a substrate bearing a 3-CF3 group afforded monoalkenylated product 7a (entry 12), which is consistent with the result of the reaction with acrylate. To our delight, the reactions can be easily performed on a large scale; for example, 3a and 6a were isolated in 86% (Scheme 2) and 70% yields (Table 2) on a 3.0 mmol scale, respectively. Since the N-acyl sulfonamide directing group is relatively labile, it can be easily removed under mildly basic conditions to give 8 (eq 1). The double bond of the enesulfonamide 8 and 6a can be reduced by NiCl2·6H2O/
smoothly, leading to the formation of monoalkenylated cyclization products 4c−f. Moreover, various acrylates, including methyl acrylate, butyl acrylate, benzyl acrylate, and tert-butyl acrylate, efficiently reacted with 1a to produce the corresponding products 3o−r. In contrast to the acrylate, N,Ndimethylacrylamide reacted with 1a in a 1:1 ratio, resulting in the formation of cyclization product 4g. Nonetheless, other alkenes bearing electron-withdrawing groups, such as (phenylsulfonyl)ethane, diethyl vinylphosphonate, and ethyl vinyl ketone were not suitable substrates for this reaction and gave the desired products in very low yield (
Regioselective Ortho Olefination of Aryl Sulfonamide via RhodiumCatalyzed Direct C−H Bond Activation Weijia Xie,† Jie Yang,† Baiquan Wang,*,†,‡ and Bin Li*,† †
State Key Laboratory of Element-Organic Chemistry, Synergetic Innovation Center of Chemical Science and Engineering, College of Chemistry, Nankai University, Tianjin 300071, People’s Republic of China ‡ State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People’s Republic of China S Supporting Information *
ABSTRACT: Rh(III)-catalyzed ortho C−H olefination of aryl sulfonamide directed by the SO2NHAc group is reported. This oxidative coupling process is achieved highly efficiently and selectively with a broad substrate scope. The reactions of Ntosylacetamide with acrylate esters afford ortho-alkenylated benzofused five-membered cyclic sulfonamides, whereas styrenes provide the direct diolefination products.
■
INTRODUCTION Transition-metal-catalyzed C−H functionalization of arenes represents a step-economical and waste-reducing process, because no prior functionalization of the substrate is necessary.1 Its synthetic applications have been well identified in the fields of organic synthesis, medicinal chemistry, and materials science.2 In this regard, the Fujiwara−Moritani reaction3 oxidative olefination of normally inert aryl C−H bondsis an attractive alternative to the traditional Mizoroki−Heck reaction.4 Among such transformations, palladium(II) complexes have been extensively explored and widely used due to their remarkable activities.5 Later, after the pioneering work of Satoh and Miura, rhodium(III)6 and ruthenium(II)7,8 species were also found to exhibit high catalytic activity in the oxidative alkenylation reactions. In these reactions, the utility of a neighboring directing group has proven to be one of the most promising strategies for ensuring regioselective C−H activation.9 Sulfonamide functional groups have long been acclaimed as essential structural motifs presented in drugs such as darunavir, celecoxib, and gliclazide.10 Meanwhile, sultams (cyclic sulfonamides) have emerged as privileged structures in drug discovery due to their diverse biological properties.11 In particular, a number of benzofused sultams have shown promising bioactivity for treating disorders of the brain12 and exhibit broad inhibitory properties against a variety of enzymes (Figure 1).13 Recent studies reveal that the sulfonamide group can act as a directing group in promoting C−H activation; however, only very limited examples have been documented.14,15 In 1998, Miura demonstrated the olefination reaction of N-(2′-phenylphenyl)benzenesulfonamides with acrylate esters via cleavage of the C−H bond at the 2′position.15a In 2011, Li reported a rhodium(III)-catalyzed C−H © XXXX American Chemical Society
Figure 1. Biologically active molecules containing the sulfonamide or sultam substructure motif.
olefination of N-(1-naphthyl)sulfonamides at the peri position.15b Later, this group described a Rh(III)-catalyzed oxidative coupling between N-allyl sulfonamides with activated olefins.15c For these substrates, the C−H bonds of arenes connected to sulfonamide sulfur atoms are totally inert under the reaction conditions (Scheme 1). With the assistance of SO2NHC6F5 as a directing group, Yu reported Pd-catalyzed sulfonamide C−H olefination. The reactions only produce direct alkenylation products, irrespective of the alkenes employed (Scheme 1a).15d As a continuation of our interest in Ru- and Rh-catalyzed C−H functionalization,16 we herein disclose our recent development of Rh-catalyzed regioselective oxidative C−H olefination using SO2NHAc as a directing Received: July 9, 2014
A
dx.doi.org/10.1021/jo5015239 | J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry
Article
Scheme 1. Sulfonamide Group Directed Oxidative Olefination
Table 1. Optimization of Oxidative Coupling between 1a and 2aa
catalyst
oxidant (amt (equiv))
solvent
yield (%)b
1 2 3 4 5 6
[Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2
toluene DME CH3CN toluene toluene toluene
99 (93)c 10 NR trace 48 trace
7 8 9 10 11 12
[Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*Rh(OAc)2] [Cp*RhCl2]2/ AgSbF6 none [Ru(p-cymene) Cl2]2
Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O Ag2CO3 AgOAc Cu(OAc)2·H2O (0.5) + O2 Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O
toluene toluene toluene toluene toluene toluene
82d 54e 40f NRg 65h NRi
Cu(OAc)2·H2O Cu(OAc)2·H2O
toluene toluene
NR NR
entry
group. The reactions afford ortho-alkenylated benzofused sultam analogues and diolefinated aryl sulfonamides with good yields and a broad reaction scope (Scheme 1b).
13 14
■
a Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol). bYield determined by 1H NMR (internal standard: 1,1,2,2-tetrachloroethane). NR = no reaction. cValue in parentheses indicates yield after purification. d2.0 mol % of [Cp*RhCl2]2 was used. e1a:2a (1:1); the monoalkenylated cycloadduct was also formed in 16% yield. f1a:2a (2:1), 2a (0.3 mmol); the monoalkenylated cycloadduct was also formed in 25% yield. g80 °C. h4.0 mol % of [Cp*Rh(OAc)2] was used. i 12.0 mol % of AgSbF6 was used.
RESULTS AND DISCUSSION We initiated our study with the oxidative olefination of readily available N-tosylacetamide (1a) and ethyl acrylate (2a). After a considerable number of experiments (Table 1),17 we found that product 3a, which was formed by dialkenylation at both ortho positions followed by intramolecular hydroamination, was obtained in 93% yield in the presence of [Cp*RhCl2]2 (3.0 mol %) and Cu(OAc)2·H2O (2.0 equiv) in toluene at 100 °C under an Ar atmosphere for 24 h (entry 1, Table 1). No monoalkenylated cycloadduct was observed. The structure of 3a was confirmed by 1H and 13C NMR analysis and mass spectrometry. The solvents DME and CH3CN exhibited negative results (entries 2 and 3). A change of oxidant to AgOAc, Ag2CO3, or O2 led to a low yield or a trace amount of the desired product (entries 4−6). Reducing the amount of [Cp*RhCl2]2 from 3.0 to 2.0 mol % provided 3a in 82% yield (entry 7). It is interesting to find that when switching the ratio of 1a and 2a to 1:1 and 2:1, the reactions still gave dominantly the dialkenylation product 3a and the monoalkenylated cycloadduct was detected in 16% and 25% yields by 1H NMR, respectively (entries 8 and 9). The reaction efficiency was also sensitive to the reaction temperatures (entry 10). Some other rhodium complexes were also screened. For example, when [Cp*Rh(OAc)2] was applied as a catalyst, the reaction still afforded dialkenylation product 3a, albeit in relatively lower yield (entry 11). However, the cationic rhodium species [Cp*Rh(MeCN)3][SbF6]2, generated in situ by the addition of AgSbF6, totally inhibited the reaction (entry 12). A control experiment confirmed that the transformation did not proceed in the absence of the rhodium catalyst (entry 13). Finally, [Ru(p-cymene)Cl2]2 displayed no catalytic activity under the present reaction conditions (entry 14). With the promising optimal conditions, we first investigated the influence of different substituents on the sulfonamide nitrogen atom (Scheme 2). In addition to the acetyl group, the butyryl group was also well suited and gave the product 3b
under the optimized reaction conditions in 97% yield. However, the pivaloyl, N-methoxy, and N-acrylyl derivatives were completely unreactive. We next examined the scope of aryl sulfonamides with diverse arene substituents (Scheme 2). Gratifyingly, the reaction proceeded smoothly irrespective of the electronic nature of the substituents to afford the desired products in good to excellent yields. Many important functional groups, such as fluoro, chloro, bromo, methoxy, trifluoromethoxy, and ester substituents, were compatible in the present catalytic reaction (3d−i). Surprisingly, in addition to the desired product 3j, a substrate with a nitro substituent also afforded the nitro group reduced byproduct 3k in 16% yield. This result suggested that the nitro group might partially act as an oxidant in this reaction. The meta-substituted substrates were then studied. Both naphthalen-2-yl and 3-bromophenyl sulfonyl acetamide reacted with acrylates to form 3l−n as the sole products. Interestingly, the cyclizations occurred at the sterically more hindered position in compounds 3l−n, which were confirmed by NOESY spectroscopy of 3l,m.17 The exact reason for the selective ring formation is not clear yet, although it seems that the adjacent steric hindrance of meta-substituted group to the alkene could be partially involved. Notably, a substrate bearing a 3-CF3 moiety underwent the olefination to provide monoolefinic products 4a,b in moderate yield. The monofunctionalization in 4a,b might result from the combined electronic and steric effects of the meta-substituted CF3 group. Ortho-substituted aryl sulfonamides coupled with ethyl acrylate B
dx.doi.org/10.1021/jo5015239 | J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry
Article
Scheme 2. Rhodium-Catalyzed Oxidative C−H Olefination with Acrylic Acid Estersa
a Reaction on a 0.3 mmol scale. Yields of isolated products are given. NR = no reaction. bThe value in parentheses indicates the yield of the reaction on a 3.0 mmol scale. c5.0 mol % of [Cp*RhCI2]2 was used. d2.0 equiv of 2 was used. eAt 120 °C.
the dialkenylated derivative 6a in 81% yield (entry 1, Table 2). In this reaction, no cyclization process occurred. Under the reaction conditions, various substituted styrenes with either electron-donating or -withdrawing groups were good candidates and produced the corresponding products 6b−h in moderate to high yield (entries 2−8). The reaction is also tolerant of different substitutions on the aromatic sulfonamides. For example, 4-chloro- and 4-methoxy-substituted aryl sulfonamides also reacted well with 5a (entries 9 and 10). Examination of the meta-substituted substrate scope revealed that 3-bromophenyl sulfonyl acetamide only produced dialkenylated derivative 6k, albeit in low yield (entry 11). However, the reaction of a substrate bearing a 3-CF3 group afforded monoalkenylated product 7a (entry 12), which is consistent with the result of the reaction with acrylate. To our delight, the reactions can be easily performed on a large scale; for example, 3a and 6a were isolated in 86% (Scheme 2) and 70% yields (Table 2) on a 3.0 mmol scale, respectively. Since the N-acyl sulfonamide directing group is relatively labile, it can be easily removed under mildly basic conditions to give 8 (eq 1). The double bond of the enesulfonamide 8 and 6a can be reduced by NiCl2·6H2O/
smoothly, leading to the formation of monoalkenylated cyclization products 4c−f. Moreover, various acrylates, including methyl acrylate, butyl acrylate, benzyl acrylate, and tert-butyl acrylate, efficiently reacted with 1a to produce the corresponding products 3o−r. In contrast to the acrylate, N,Ndimethylacrylamide reacted with 1a in a 1:1 ratio, resulting in the formation of cyclization product 4g. Nonetheless, other alkenes bearing electron-withdrawing groups, such as (phenylsulfonyl)ethane, diethyl vinylphosphonate, and ethyl vinyl ketone were not suitable substrates for this reaction and gave the desired products in very low yield (
